Heteroaryl sulfonamides and CCR2/CCR9

• US 10,206,912 B2
• Filed: 12/19/2016
• Issued: 02/19/2019
• Est. Priority Date: 07/14/2006
• Status: Active Grant

• Current Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Original Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Inventors: Ungashe, Solomon, Wei, Zheng, Basak, Arindrajit, Charvat, Trevor T., Chen, Wei, Jin, Jeff, Moore, Jimmie, Zeng, Yibin, Punna, Sreenivas, Dairaghi, Daniel, Hansen, Derek, Pennell, Andrew M. K., Wright, John J., Krasinski, Antoni, Wang, Qiang
• Primary Examiner(s): Reese, Heidi
• Application Number:
  US15/383,788
• Publication Number:
  US 20170095458A1
• Time in Patent Office: 792 Days
• Field of Search: None
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 241/22 Benzenesulfonamido pyrazines
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

Abstract

Compounds are provided that act as potent antagonists of the CCR2 receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR2. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR2-mediated diseases, and as controls in assays for the identification of CCR2 antagonists.

Claims

1. A method for treating a CCR2-mediated condition or disease comprising administering to a subject an effective amount of a compound of formula (Ie), or a salt thereof:

2. The method of claim 1, wherein L is —

C(O)—

.

3. The method of claim 1 wherein X³ and X⁴ are each independently halogen or C_1-8 haloalkyl.

4. The method of claim 1 wherein X², X⁵, and X⁶ are each H.

5. The method of claim 1, wherein R¹ is hydrogen.

6. The method of claim 1 wherein Y⁶ is unsubstituted C_1-8 alkyl.

7. The method of claim 1 wherein Y⁷ is H.

8. The method of claim 1 wherein Y⁴ is —

N—

, or —

N+(O)⁻

—

.

9. The method of claim 1 wherein Z⁶ and Z⁷ are —

CH—

.

10. The method of claim 1 wherein Z⁵ is —

N—

.

11. The method of claim 1 wherein R¹⁰⁰ is hydrogen.

12. The method of claim 1, where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

13. The method of claim 1, further comprising administering an anti-inflammatory or analgesic agent.

14. The method of claim 1, further comprising administering an opiate agonist, a lipoxygenase inhibitor, an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, a cyclooxygenase-2 inhibitor, an interleukin inhibitor, an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide, an inhibitor of the synthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or a cytokine-suppressing anti-inflammatory agent, a biological TNF sequestrant, an H2-antagonist, a decongestant, an antitussive, a diuretic;

a sedating or non-sedating antihistamine;

a very late antigen (VLA-4) antagonist;

an immunosuppressant, a steroid;

a non-steroidal anti-asthmatic agent, a beta 2-agonist, a leukotriene antagonist, a leukotriene biosynthesis inhibitor;

an inhibitor of phosphodiesterase type IV (PDE-IV), a cholesterol lowering agent, a HMG-CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-diabetic agent, a-glucosidase inhibitor, a corticosteroid, a lubricant, a keratolytic agent, a vitamin D3 derivative or a beta 2-agonist.

15. The method of claim 1 wherein the compound is of the formula (Ig):

16. The method of claim 1 wherein the compound is of the formula (If):

17. The method of claim 1, where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

18. The method of claim 17, further comprising administering an anti-inflammatory or analgesic agent.

25. The method claim 1, wherein the CCR2-mediated disease or condition is selected from the group consisting of pulmonary fibrosis, transplantation rejection, graft-versus-host disease, and cancer.

19. A method for treating a CCR2-mediated condition or disease comprising administering to a subject an effective amount of a compound selected from the group consisting of:

26. The method claim 19, wherein the CCR2-mediated disease or condition is selected from the group consisting of pulmonary fibrosis, transplantation rejection, graft-versus-host disease, and cancer.

20. A method for treating a CCR2-mediated condition or disease comprising administering to a subject an effective amount of a compound of the following formula or a salt thereof:

21. The method of claim 20 where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

22. The method of claim 20, further comprising administering an anti-inflammatory or analgesic agent.

23. The method of claim 20, further comprising administering an opiate agonist, a lipoxygenase inhibitor, an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, a cyclooxygenase-2 inhibitor, an interleukin inhibitor, an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide, an inhibitor of the synthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or a cytokine-suppressing anti-inflammatory agent, a biological TNF sequestrant, an H2- antagonist, a decongestant, an antitussive, a diuretic;

a sedating or non-sedating antihistamine;

a very late antigen (VLA-4) antagonist;

an immunosuppressant, a steroid;

a non-steroidal anti-asthmatic agent, a beta 2-agonist, a leukotriene antagonist, a leukotriene biosynthesis inhibitor;

an inhibitor of phosphodiesterase type IV (PDE-IV), a cholesterol lowering agent, a HMG-CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-diabetic agent, a-glucosidase inhibitor, a corticosteroid, a lubricant, a keratolytic agent, a vitamin D3 derivative or a beta 2-agonist.

24. The method claim 20, wherein the CCR2-mediated disease or condition is selected from the group consisting of pulmonary fibrosis, transplantation rejection, graft-versus-host disease, and cancer.